The neural bases of cognitive symptoms in Parkinson's disease (PD) are not well understood, nor are the effects of dopamine (DA) therapy, which can be neutral, beneficial, or detrimental. Cognitive symptoms in PD can be related to the distinction between cognitive stability and flexibility mechanisms, which are thought to depend on the opposing roles of the prefrontal cortex (PFC) and striatum, respectively. Cognitive stability is a component of working memory that involves encoding and maintenance of representations in the face of distraction. Cognitive flexibility involves updating and integrating information in working memory. Although it is unclear whether DA therapy improves stability and flexibility deficits in PD, the neural substrates of these mechanisms are linked to the expression of genes that are related to baseline levels of DA in the brain and cognitive proficiency. Thus, the neurobehavioral response to DA therapy in PD may depend on the expression of these genes. This project will use fMRI to identify disease-related patterns of activity in PD that disrupt the stability and flexibility of timing, which is a predictive process that also depends on DA and is vital for cognition and movement. Objectives 1 and 2 will identify the neural bases of deficits in timing stability and flexibility in PD. Objective 3 will determine the effect of DA therapy on timing stability and flexibility and their neural substrates. Objective 4 will determine if COMT val158met and BDNF val66met expression distinguish the response of the PFC (stability) and striatum (flexibility) to DA therapy in PD. In each experiment, 24 healthy adults and 24 individuals with PD will be tested as they undergo fMRI while performing tasks that probe for stability (Experiment 1) and flexibility (Experiment 2) effects on temporal cognition. PD volunteers will be tested once after they stop their DA therapy overnight so that they are in a practical 'off state, and once after taking their normal DA therapy to evaluate the effect of medication on neurobehavioral functioning. It is predicted that disease- related patterns of PFC and striatal activation in PD will differ during probes for timing stability and flexibility. Neurobehavioral responses to DA therapy are expected to depend on the expression of COMT val158met in the PFC and BDNF val66met in the striatum. This research is expected to identify the neural markers for key components of cognitive dysfunction in PD. Insight into the influence of genetic factors on neurobehavioral responses to DA therapy is crucial for elucidating complex physiological and pharmacotherapy interactions that could guide individualized treatments and influence drug development. PUBLIC HEALTH RELEVANCE: This proposal responds to the CSR&D Program solicitation for research in PD. The prevalence of PD is 1% to 3% in adults over the age of 65, making it second only to Alzheimer's disease as a neurodegenerative disorder. The incidence in the veteran population is likely to increase further due to head injuries in veterans returning from Afghanistan and Iraq, as people who experience neurotrauma are four to eight times more likely to develop idiopathic PD. As such, with a larger proportion of the population aging, the numbers of people with PD can be expected to increase substantially by the year 2020, placing even greater demands on the VA health care system. The present proposal's focus on cognitive disabilities in PD is therefore timely and long overdue, as treatment approaches for cognitive dysfunction in PD are largely overlooked, despite an incidence of about 50% early in the disease. Many people with PD eventually develop dementia, which is three to four times more prevalent than in normal aging. As such, it is vital to understand cognitive disabilities in PD, their neuronal bases, and their responsiveness to DA therapy, which remains the main pharmacotherapeutic approach. The role that genetic factors play in determining neural-cognitive responses to DA therapy is also critical for understanding the considerable individual differences in the effect of DA treatment on cognitive dysfunction. This knowledge could promote more optimal, individualized treatments and drive the development of new medication treatments.